The research goal of our laboratory is to understand the molecular mechanism of tumor necrosis factor (TNF) signaling and the regulation of cell death and the role of cell death in tumorigenesis. Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a critical role in diverse cellular events, including cell proliferation, differentiation, and cell death. TNF is also involved in many types of diseases, including cancer. Inappropriate production of TNF plays a critical role in the pathogenesis of both acute and chronic inflammatory diseases such as septic shock, acquired immunodeficiency syndrome (AIDS), and arthritis. The development of anti-TNFalpha therapy is arguably the most significant achievement in the treatment of autoimmune-diseases, such as rheumatoid arthritis and Crohn's disease. Opposing effects of TNF on cancer have been described: a high dose of TNF (acute inflammation) has anti-neoplastic effects, such as direct cytotoxicity on certain types of cancer, while an endogenous low-dose of TNF (chronic inflammation) promotes cancer development. Studies from many laboratories have demonstrated that the diverse TNF-mediated biological responses are achieved through activating multiple signaling pathways (see below). Although much information about TNF signaling has been obtained in recent years, many molecular aspects of TNF signaling and its role in inflammation and cancer development remain unknown. Therefore, uncovering the molecular mechanism of TNF signaling will not only shed new light on the physiological regulation of TNF function but also help to understand its role in inflammation and cancer development. In last year, we have made several significant contributions to the understanding of the molecular mechanism regulating TNF signaling and the regulation of cell death. In the future, we will continue to investigate the regulation of TNF signaling, particularly the molecular mechanisms of TNF-induced cell death, and to explore the role of cell death in tumorigenesis as specified in the following: Studying the regulation of TNF-induced cell death and the involvement of key cell death regulatory proteins in tumorigenesis Aim1: Investigating the regulation of TNF-induced apoptosis by the novel anti-apoptotic protein, ATIA, and its potential role in tumorigenesis. a) Understanding the underlying mechanism of the anti-apoptotic effect of ATIA. b) Demonstrating the importance of ATIA in tumorigenesis. Aim 2: Identifying and studying novel players in TNF-induced necroptosis and exploring the role of necroptosis in tumorigenesis. Understand the regulation of TNF-induced necroptosis. a) Investigate the mechanism of MLKL-mediated necroptosis. b) identifying new components of TNF-induced necroptosis including RARgamma. Study the role of tumor necrosis in tumor development and tumor metastasis. Most recently, we have found that necroptosis of tumor cells leads to tumor necrosis and promotes tumor metastasis. RARgamma is down-regulated in skin cancer and may function as a tumor suppressor. we found that RARgamma plays a critical role in DNA damage-induced necroptosis.